16-16-dimethylprostaglandin-e2 and Body-Weight

In this study, we evaluated the protective effect and therapeutic potential of the prostaglandin E(2) (PGE(2)) synthetic analog 16,16-dimethyl-PGE(2) (dmPGE(2)) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intratracheal administration of bleomycin (1 mg/kg) received a dmPGE(2) dose of 30 microg/kg/day by continuous subcutaneous infusion. Bronchoalveolar lavage (BAL); immunohistochemical analysis for IL-1, TNF-alpha, and nitrotyrosine; measurement of fluid content in lung; myeloperoxidase activity assay; and lung histology were performed 1 week later. Lung histology and Sircol assay for collagen deposition were performed 3 weeks after treatments. Changes of body weight and survival rate were also evaluated at 1 and 3 weeks. Compared with bleomycin-treated mice, dmPGE(2) co-treated mice exhibited a reduced degree of body weight loss and mortality rate as well as of lung damage and inflammation, as shown by the significant reduction of: (1) lung infiltration by leukocytes; (2) myeloperoxidase activity; (3) IL-1, TNF-alpha, and nitrotyrosine immunostaining; (4) lung edema; and (5) histologic evidence of lung injury and collagen deposition. In a separate set of experiments, dmPGE(2) treatment was started 3 days after bleomycin administration, and the evaluation of lung damage and inflammation was assessed 4 days later. Importantly, delayed administration of dmPGE(2) also was able to protect from inflammation and lung injury induced by bleomycin. These results, indicating that dmPGE(2) is able to prevent and to reduce bleomycin-induced lung injury through its regulatory and anti-inflammatory properties, encourage further research to find new options for the treatment of pulmonary fibrosis.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Collagen; Disease Models, Animal; Infusions, Subcutaneous; Interleukin-1beta; Lung; Lung Injury; Male; Mice; Peroxidase; Pneumonia; Protective Agents; Pulmonary Edema; Pulmonary Fibrosis; Time Factors; Tumor Necrosis Factor-alpha; Tyrosine

We examined the HCO(3)- stimulatory effects of L-NAME (N(G)-nitro-L-arginine methyl ester) in the proximal duodenum of streptozotocin (STZ)-induced diabetic rats and compared with those of 16,16-dimethyl prostaglandin E2 (dmPGE2) and vagal electrical stimulation. Male SD rats were given STZ (70 mg/kg) i.p., and the experiments were done using 1 approximately 6 week STZ-diabetic rats with blood glucose levels of >300 mg/dl. Under urethane anesthesia the HCO(3)- secretion was measured in the proximal duodenal loop using a pH-stat method and by adding 10 mM HCl. Hyperglycemic conditions appeared 1 week after STZ treatment and remained during 6 week-test period. The duodenal HCO(3)- secretory response to L-NAME was significantly decreased in STZ-diabetic rats; the degree of reduction was dependent on the duration of diabetes, and the stimulatory effect disappeared completely in rats after 5 approximately 6 weeks of diabetes. Intravenous administration of L-NAME markedly increased arterial blood pressure with significant decrease in heart rate in normal rats, whereas in STZ-diabetic rats this agent caused only pressor response without any effect on heart rate. STZ-diabetic rats also secreted significantly less amount of HCO(3)- from the duodenum in response to dmPGE2 and vagal electrical stimulation after 5 approximately 6 weeks of diabetes. These all changes observed in STZ-diabetic rats were significantly reversed by daily injection of insulin. These results suggest that 1) L-NAME failed to stimulate duodenal HCO(3)- secretion in STZ-diabetic rats, and 2) impairment of the duodenal HCO(3)- secretory ability in STZ-diabetic conditions is due to both vagal-dependent neuronal dysfunction and decreased sensitivity of the secreting cell.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Bicarbonates; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Duodenum; Electric Stimulation; Enzyme Inhibitors; Heart Rate; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Vagus Nerve

Liver fibrosis was induced in rats by repeated peritoneal injections of carbon tetrachloride (CCl4) over a period of 2-11 weeks. Serum procollagen III peptide (SPIIINP), prolidase (SP) and alanine aminotransferase (SALT) levels were monitored during the period of induction. The extent of fibrosis was semi-quantitatively estimated after collagen staining, and the anti-fibrotic effects of 16,16-dimethyl prostaglandin E2 (DMPGE2), colchicine, and zinc sulphate were studied. SPIIINP and SP were increased the first 2 weeks after CCl4 administration and peaked at 6 weeks. Alterations in SPIIINP and SP correlated well to the semi-quantitative histological score of liver sections during the first 6 weeks, and SP was positively related to SPIIINP throughout the whole induction period. DMPGE2 decreased SPIIINP, SP and SALT significantly in addition to a markedly decreased formation of liver collagens. Colchicine had a similar but less dramatic effect, whereas zinc sulphate only reduced SPIIINP without influencing liver damage. In conclusion SPIIINP seems to be a valuable indicator of liver fibrogenesis, and SP may play a limited role in indicating accelerated collagen metabolism in the liver. DMPGE2 obviously inhibited the production of collagens induced by CCl4. Colchicine also had an apparent effect on liver fibrosis, whereas zinc sulphate merely seemed to postpone it.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Biomarkers; Body Weight; Carbon Tetrachloride; Colchicine; Female; Liver; Liver Cirrhosis, Experimental; Male; Monitoring, Physiologic; Organ Size; Rats; Rats, Sprague-Dawley; Sulfates; Zinc; Zinc Sulfate

The effect of an exogenous synthetic prostaglandin analogue, 16,16-dimethyl prostaglandin E2 (16,16-dm-PGE2), as well as the effect of endogenous prostaglandin synthesis inhibition by a cyclooxygenase inhibitor, flurbiprofen, on chemically induced gastric carcinogenesis has been investigated in rats. Carcinogenesis was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS:70-25-7). Animals were divided into six groups: Group I, treatment with MNNG alone; Group II, treatment with 16,16-dm-PGE2 plus MNNG; Group III, treatment with flurbiprofen plus MNNG; Group IV, treatment with 16,16-dm-PGE2 alone; Group V, treatment with flurbiprofen alone; and Group VI, controls. Treatment with high doses of MNNG resulted in rapid development of malignant tumors originating from the glandular epithelium of the stomach and duodenum in animals of all groups receiving the carcinogen. The first gastric adenocarcinoma infiltrating the muscularis proper was detected after 139 days in an animal treated with a combination of MNNG and flurbiprofen. The incidence of infiltrating adenocarcinoma and the incidence of all neoplastic lesions of the glandular stomach were both significantly higher in animals treated with a combination of MNNG and flurbiprofen compared with treatment by MNNG alone or in combination with 16,16-dm-PGE2 (P less than 0.05 and P less than 0.001). The difference in tumor incidence between the last two groups was not significant. The first duodenal adenocarcinoma was detected on Day 114 in another animal of the group treated with MNNG plus flurbiprofen. When compared with the group treated with MNNG plus 16,16-dm-PGE2, significantly more animals developed duodenal adenocarcinoma when treated with MNNG plus flurbiprofen (P less than 0.005) or with MNNG alone (P less than 0.05). Results of this study indicate that inhibition of endogenous prostaglandin synthesis favors development of adenocarcinoma in the glandular stomach of rats. Vice versa, the addition of an exogenous prostaglandin analogue inhibits the development of duodenal adenocarcinoma. This protective effect of prostaglandins may be due to an increase of the thickness of the mucus gel covering the glandular epithelium, thereby preventing access of carcinogen to the mucosa.

Topics: 16,16-Dimethylprostaglandin E2; Adenocarcinoma; Animals; Body Weight; Duodenal Neoplasms; Female; Flurbiprofen; Gastric Mucosa; Methylnitronitrosoguanidine; Prostaglandins; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Neoplasms

To determine whether a serum parameter of collagen metabolism, serum procollagen type III peptide, correlated with hepatic collagen in a model of diet-induced fibrosis, rats were fed a control or cirrhogenic diet for 6 months and treated with either subcutaneous vehicle or the hepatoprotective prostaglandin 16,16-dimethyl prostaglandin E2 (100 micrograms per kg) twice daily. Pair-fed rats from each group were killed after 2, 4 or 6 months. The value of serum procollagen type III peptide to body weight integrated over time (Kt) correlated linearly with hepatic hydroxyproline content (r = 0.97) at killing time t. Good correlations were also seen between Kt and histopathological assessment of aniline blue-stainable collagen (r = 0.93) and between the histopathology and hydroxyproline content (r = 0.97). Rats receiving 16,16-dimethyl prostaglandin E2 had lower values of all three parameters compared to rats receiving vehicle, confirming the previously demonstrated hepatoprotective effect of 16,16-dimethyl prostaglandin E2. The excellent correlation between Kt and the two other traditional parameters of hepatic collagen suggest that sequential measurements of serum procollagen type III peptide can be used to predict alterations in liver collagen deposition in rats.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Body Weight; Collagen; Deficiency Diseases; Disease Models, Animal; Hydroxyproline; Liver; Liver Cirrhosis, Experimental; Male; Peptide Fragments; Predictive Value of Tests; Procollagen; Rats; Rats, Inbred Strains; Time Factors

We investigated whether the trophic actions of prostaglandins, omeprazole, and indomethacin on gastric mucosa lead to accelerated healing of gastric ulcers in the rat. Cryoulcers were produced in the corpus area and treated with 16,16-dimethyl prostaglandin E2 (5 or 100 micrograms/kg b.i.d., intragastrically), omeprazole (40 mumol/kg once daily, subcutaneously), indomethacin (2 mg/kg b.i.d., subcutaneously), or placebo. At the end of the treatment, plasma gastrin, cell labeling index (autoradiography with [3H]thymidine), and the size and depth of mucosal defects were measured. Compared with placebo, omeprazole accelerated ulcer healing as indicated by a smaller ulcer area [1.1 +/- 0.2 vs. 4.8 +/- 1.2 mm2 (mean +/- SEM)] and smaller ulcer depth (383 +/- 31 vs. 488 +/- 41 microns) after 10 days of treatment. Prostaglandins did not affect ulcer healing despite thickening of gastric corpus mucosa. Indomethacin delayed ulcer healing and reduced the labeling index. Omeprazole induced a marked hypergastrinemia (208 +/- 12 vs. 66 +/- 12 pmol/L on day 5, and 469 +/- 23 vs. 58 +/- 16 pmol/L on day 10). The results indicate that abolishment of acid secretion by omeprazole accelerates healing. Trophic actions and "cytoprotective" effects by prostaglandins are not relevant for ulcer healing in this model.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Autoradiography; Body Weight; Gastric Mucosa; Gastrins; Indomethacin; Male; Omeprazole; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

Several markers of growth and biochemical development in the rat were studied after administration of prostacyclin (PGI2) and 16, 16-dimethyl prostaglandin E2 (16, 16DM PGE2). Intermittent administration of PGI2 for 3 days to 10- and 19-day-old animals, with subsequent sacrifice at 14 and 23 days, resulted in significant dose related decreases in growth at 23 days. Total sucrase and maltase (glucoamylase) activities were elevated compared to controls at 14 days. Total activities of these enzymes were decreased in postweaned 23-day-old animals, but specific activities per mg intestinal protein were not significantly different. 16, 16DM PGE2 administered continuously between day 10-16 of life caused alterations in growth as well as increases in sucrase and maltase (glucoamylase) activities. Exogenously administered prostaglandins, therefore, are associated with altered growth and markers of biochemical development in the rat.

Topics: 16,16-Dimethylprostaglandin E2; alpha-Glucosidases; Animals; beta-Galactosidase; Body Weight; Epoprostenol; Growth; Intestinal Mucosa; Intestines; Liver; Organ Size; Prostaglandins E, Synthetic; Proteins; Rats; Sucrase